Lactylation at the crossroads of metabolism and epigenetics in neuroinflammation

作者：Hao Wang, Kangmei Shao, Ran Zhou, Jiajia Xi, Wen Zhang, Yazhen Hao, Jingjing Song, Zhaoming Ge · 发表于：Frontiers in Immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1784112 · 被引用次数：1 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neurogenesis and neuroplasticity mechanisms、Amyotrophic Lateral Sclerosis Research

Lactate has moved from being viewed as an inert glycolytic end-product to a pleiotropic metabolite that shapes cellular signaling and gene regulation. A major inflection point is the identification of lysine lactylation (Kla), a post-translational modification that can couple glycolytic state to chromatin remodeling and protein function. In the central nervous system, lactate production, compartmentalization, and transport-coordinated by cell-type-specific expression of lactate dehydrogenases and monocarboxylate transporters within the neurovascular unit-create dynamic microenvironments that are increasingly recognized as determinants of neuroinflammatory tone. Emerging evidence indicates that Kla occurs on both histone and non-histone substrates and can reprogram inflammatory and stress-response networks in microglia, astrocytes, endothelial cells, and neurons, intersecting with canonical pathways such as NF-κB, inflammasome signaling, and cytokine-driven transcriptional programs. However, the field faces key mechanistic and translational gaps, including incomplete definition of Kla "writers/erasers/readers," uncertainty about the quantitative relationship between lactate flux and site-specific lactylation, and marked context dependence across disease stage, cell state, and brain region. This review integrates current understanding of CNS lactate metabolism and trafficking with the expanding landscape of Kla biology, synthesizes cell- and disease-specific evidence across acu...